The purpose of this project is to investigate the ability of the neonatal liver to regulate glucose output under a variety of substrate and hormonal influences. Whether the fasted newborn liver can intrinsically regulate glucose output or can generate glucose from lactate or alanine is not known. The newborn piglet is the model for these studies because: 1) it has a phosphoenolpyruvate carboxykinase enzyme distribution similar to man, and; 2) in contrast to the rat, the pig appears to be remarkably similar to man in the mechanisms responsible for gluconeogenic control. It is our hypothesis that the newborn piglet responses to glucoregulatory effectors (glucagon and epinephrine) are immature and are coupled with an imprecise C.N.S. control of glucose homeostasis. We further hypothesize that fatty acid oxidation and its products will inhibit gluconeogenesis from lactate during the first few days of life. To test these hypotheses, we will use isolated liver perfusions to delineate intrinsic hepatic glucose regulation; gluconeogenic response to glucagon and epinephrine; and the effect of fatty acid oxidation or its products on gluconeogenesis at 1 and 5 days of age. Mitochondrial phosphoenolpyruvate formation and the role of acylcarnitines on pyruvate utilization by mitochondrial will be assessed with each hepatic effector or substrate studied. The role of the C.N.S. in the control of hepatic glucose output by the liver will be studied using 2-deoxyglucose, gamma and beta blockers, and hexamethonium in intact animals. These studies will provide insight into the development of glucose regulatory mechanisms in the newborn.